
Hexanoic acid derived statins of general formula (1) or salts thereof inhibit the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) and are thus useful as a hypolipidemic and hypocholesterolemic agents.

Examples of these statins are atorvastatin wherein R1 is a radical of formula (A), cerivastatin wherein R1 is a radical of formula (C), fluvastatin wherein R1 is a radical of formula (F), pitavastatin wherein R1 is a radical of formula (P) and rosuvastatin wherein R1 is a radical of formula (R).
For the introduction of the chiral part of the abovementioned molecules, intermediates of general formula (2) play a pivotal role.

In the compounds of general formula (2) X stands for halogen and R2 and R3 each independently stand for an alkyl with for instance 1 to 12 carbon atoms and R2 and R3 may form a ring together with the carbon atom to which they are bound. The group R4 is a carboxylic acid protecting group. For preparative purposes, R4 must be a group that can be easily removed after formation of the statin structure. Suitable groups in this respect have proven to be sec-butyl, tert-butyl, iso-propyl and the like. In WO 02/06266 a procedure is disclosed for the preparation of compounds of formula (2) wherein R4 is a methyl group, starting from a compound of general formula (3), with X is defined as above, by reaction with commercially available dimethoxypropane.

Unfortunately methyl protection is less suitable in the subsequent chemistry towards statins. To this end also the preparation of alternate esters that are preferred in view of ease of removal of impurities, reduction of side-reactions and/or stability is disclosed in WO 02/06266. However, this approach requires three additional reaction steps, namely hydrolysis of the methyl ester, activation of the resulting acid and conversion to the ester. Hence, there is a need for an improved approach for the synthesis of compounds of general formula (2) wherein R4 is not methyl.